Circular RNAs (circRNAs) are a new member of noncoding RNAs (ncRNAs) that have recently been described as key regulators of gene expression. Our previous study had identified the negative correlation between circHIPK3 and bladder cancer grade, invasion, as well as lymph node metastasis. However, the roles of circRNAs in cellular proliferation in bladder cancer remain largely unknown. We had analyzed circRNA high-throughout sequencing from human tissues and determined bladder cancer related circRNA-3 (BCRC-3, GenBank: KU921434.1) as a new candidate circRNA derived from PSMD1 gene. The expression levels of circRNAs, mRNAs and miRNAs in human tissues and cells were detected by quantitative real-time PCR (qRT-PCR). The effects of BCRC-3 on cancer cells were explored by transfecting with plasmids in vitro and in vivo. RNA pull down assay, luciferase reporter assay and fluorescence in situ hybridization were applied to verify the interaction between BCRC-3 and microRNAs. Anticancer effects of methyl jasmonate (MJ) were measured by flow cytometry assay, western blot and qRT-PCR. BCRC-3 was lowly expressed in bladder cancer tissues and cell lines. Proliferation of BC cells was suppressed by ectopic expression of BCRC-3 in vitro and in vivo. Mechanistically, overexpression of BCRC-3 induced the expression of cyclin-dependent kinase inhibitor 1B (p27). Importantly, BCRC-3 could directly interact with miR-182-5p, and subsequently act as a miRNA sponge to promote the miR-182-5p-targeted 3’UTR activity of p27. Furthermore, MJ significantly increased the expression of BCRC-3, resulting in an obvious up-regulation of p27. BCRC-3 functions as a tumor inhibitor to suppress BC cell proliferation through miR-182-5p/p27 axis, which would be a novel target for BC therapy.

Background and Aims: Previous studies have shown that gut microbiota is associated with bladder cancer. However, the causal relationships and potential mediating factors between the gut microbiota (GM) and bladder cancer (BCa) have not been well defined. Methods: To investigate this, we utilized summary statistics from genome‐wide association studies of gut microbiota (Dutch Microbiome Project, n = 7738), plasma metabolites (Canadian Longitudinal Study of Aging follows, n = 8096), and BCa (FinnGen Biobank R9, 2053 cases and 287,137 controls). We then conducted bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between GM and BCa, and employed a two‐step MR approach to identify potential mediating metabolites. Results: Our study revealed that three taxa, Species Bacteroides dorei, Genus Streptococcus Species and Bacteroides salyersiae, were associated with BCa, while no association was found between BCa on these three taxa. Additionally, we identified 5 plasma metabolites that were simultaneously associated with BCa and the above three taxa. Mediation analysis showed that the associations between Species Bacteroides salyersiae and BCa were mediated by N‐methylproline and X‐19299, accounting for 11.6% and 28.56% of the total effect, respectively. Furthermore, Species Bacteroides dorei, Genus Streptococcus Species and Bacteroides salyersiae potentially affected BCa through 2,3‐dihydroxypyridine, N‐palmitoyl‐sphinganine and N‐methylproline, respectively. Conclusions: Overall, our study dissected the causal relationships between GM and BCa, potentially mediated by plasma metabolites. Our study identified potential targets for treatment of bladder cancer.